The pharmacologic challenge model continues to be the major research strategy of the Unit on Geriatric Psychopharmacology. By using drugs to investigate underlying biologic function, we are testing potential diagnostic methods, while simultaneously attempting to develop new drug treatments. This past year, we concluded major studies on Alzheimer's disease, a condition with known cholinergic neuropathology, with two cholinergic agents, arecoline and nicotine. These studies follow our earlier findings of higher functional sensitivity of Alzheimer patients than normal controls or elderly depressives to the anticholinergic agent, scopolamine, which suggest that the cholinergic system in Alzheimer's disease still responds to exogenous drug manipulations. These findings have also led to the development of our latest pilot studies with non-cholinergic medications such as the serotonin agonist, m-chlorophenylpiperazine (m-CPP), and the neuropeptide, thyrotropin-releasing hormone (TRH). With the high degree of overlapping symptoms between geriatric depression and dementia, it is essential to evaluate patients carefully. Consequently, we have systematically compared and contrasted these two major geriatric disorders to ensure diagnostic accuracy and to understand better the common pathologic mechanisms. Given the lack of definitive diagnostic markers, we developed special rating scales to measure depression and daily functioning in dementia subjects. Biological specimens such as cerebrospinal fluid have also been tested to help differentiate depressed and demented patients from age-matched controls. In addition, extensive cognitive testing provides us with an important profiling tool. Together, these instruments allow us to assess the effectiveness of our ongoing medication studies and will enable us to continue our correlative and longitudinal studies in the future.